Hepatocyte nuclear factor 4-mediated activation of rat CYP3A1 gene and its modes of modulation by apolipoprotein AI regulatory protein I and v-ErbA-related protein 3

Arch Biochem Biophys. 1999 Feb 1;362(1):32-7. doi: 10.1006/abbi.1998.1012.

Abstract

CYP3A1 gene (P450/6betaB) encodes testosterone 6beta-hydroxylase (EC 1.14.14.1) in rats. The promoter region of CYP3A1 gene contains three binding sites for nuclear factors: 6betaB-A (-105 to -86), 6betaB-B (-139 to -118), and 6betaB-C (-164 to -145). The 6betaB-A site shows a high degree of similarity to a consensus sequence of the binding site of hepatocyte nuclear factor 4 (HNF-4) and also to the 6betaA-A site on the rat CYP3A2 gene promoter region. Our previous study suggested an involvement of the 6betaA-A site in the basal transactivation of CYP3A2 gene using HepG2 cells. In the present study, transactivation through the 6betaB-A and 6betaA-A sites of CYP3A1 and CYP3A2 genes has directly been shown by coexpression of HNF-4 and CYP3A1 or CYP3A2 promoter-reporter fused genes. Similar experiments further showed that nuclear factor binding at the 6betaB-B site hampered HNF-4-mediated transactivation of CYP3A1 gene. Recombinant apolipoprotein AI regulatory protein I (ARP-1) and v-ErbA-related protein 3 (EAR-3) are shown to suppress HNF-4-mediated activation at the 6betaB-B site without competition of HNF-4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Base Sequence
  • Binding, Competitive / genetics
  • COS Cells
  • COUP Transcription Factor I
  • COUP Transcription Factor II
  • COUP Transcription Factors
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Hepatocyte Nuclear Factor 4
  • Mixed Function Oxygenases / genetics*
  • Molecular Sequence Data
  • Phosphoproteins / physiology*
  • Rats
  • Receptors, Steroid / metabolism
  • Repressor Proteins / physiology
  • Sequence Deletion
  • Steroid Hydroxylases / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcriptional Activation*

Substances

  • COUP Transcription Factor I
  • COUP Transcription Factor II
  • COUP Transcription Factors
  • DNA-Binding Proteins
  • Hepatocyte Nuclear Factor 4
  • Nr2f1 protein, rat
  • Nr2f2 protein, rat
  • Phosphoproteins
  • Receptors, Steroid
  • Repressor Proteins
  • Transcription Factors
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • CYP3A protein, human
  • Cyp3a23-3a1 protein, rat
  • Cytochrome P-450 CYP3A
  • steroid hormone 6-beta-hydroxylase